Periodontal diseases are a class of inflammatory diseases which if left untreated can result in soft and hard tissue destruction. While microbes are etiological agents of periodontal disease, a harmful inflammatory response in a susceptible host can exacerbate disease. Oral epithelial cells are the first line of defense against microbial infection within the oral cavity. These important cells serve multiple roles at the mucosal surface including whereby they can function as non-hematopoietic innate immune cells (in contrast to traditional hematopoietic leukocytes) that contribute directly to innate immunity and play an important role in mucosal homeostasis. Over-activation of innate immunity or disruption of this homeostasis can result in initiation and/or exacerbation of localized inflammation as seen in periodontal diseases. Thus, it is imperative that we understand epithelial cell mediated regulation of immune responses to prevent and/or treat inflammation of oral mucosa. Dynamics of TLR signaling outcomes are attributable to several factors including the type of TLR ligand(s), concentration of TLR ligand(s), duration of stimulation by TLR ligand(s), and the cell type which is being engaged by TLR ligand(s). Indeed, our preliminary data demonstrates that both human and murine oral epithelial cells respond to TLR2 stimulation in a tolerogenic manner while TLR4 stimulation induces a pro- inflammatory phenotype. Here we present preliminary data whereby targeted, inducible knockout of MYD88 (a key TLR-signaling molecule) in oral epithelial cells exacerbated soft tissue infiltration and bone loss in a multi- microbial model of periodontal disease. We propose that MYD88-dependent signaling in oral epithelial cells plays a role in controlling inflammation thus limiting localized inflammation and averting periodontal disease. It is our hypothesis that oral epithelial cell MYD88-dependent TLR signaling causes tolerogenic immune tuning which counteracts otherwise inflammatory responses. Here we will delineate mechanisms of immune tuning by oral epithelial cells during periodontal disease initiation/progression. By establishing hallmarks of disease progression we will be able to delineate checkpoints at which novel interventions can be applied to halt or reverse periodontal disease inflammation. In addition, will delineate TLR-receptor usage and signaling events which contribute to regulatory versus inflammatory epithelial cell phenotypes, allowing for the identification of targets for novel interventions aimed at attenuating oral epithelial cell associaed inflammation. Finally, will determine in vivo efficacy of an anti- inflammatory agent in an oral epithelial cell dependent model of exacerbated periodontal disease and delineate the mechanism(s) of its regulation.